1-(2-deoxy-2-fluoro-3-O-mesyl-5-O-trityl-β-D-arabinofuranosyl)-5-ethyluracil | 1251064-60-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 1-(2-deoxy-2-fluoro-3-O-mesyl-5-O-trityl-β-D-arabinofuranosyl)-5-ethyluracil
• 英文别名: [(2R,3R,4S,5R)-5-(5-ethyl-2,4-dioxopyrimidin-1-yl)-4-fluoro-2-(trityloxymethyl)oxolan-3-yl] methanesulfonate
• CAS: 1251064-60-4
• 化学式: C₃₁H₃₁FN₂O₇S
• 分子量: 594.661
• InChiKey: FUUMVUVCCZRWEY-LLNGEMMXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  120
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(2-deoxy-2-fluoro-3-O-mesyl-5-O-trityl-β-D-arabinofuranosyl)-5-ethyluracil 在 palladium 10% on activated carbon 、 水 、 氢气 、 溶剂黄146 、 三乙胺 、 sodium bromide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.5h， 生成 1-(2,3-dideoxy-2-fluoro-β-D-threopentofuranosyl)-5-ethyluracil
  参考文献：
  名称：

  Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors

  摘要：

  Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2,4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 20-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(beta-D-arabinofuranosyl)-4-thio-5hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC50 = 0.5 mu g/mL) and M. bovis (MIC50 = 0.5 mu g/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC50 = 5.0 mu g/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC50 = 1 mu g/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC50 = 10 mu g/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC50 > 100 mu g/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.004
• 作为产物：
  描述：

  2’-氟-5-乙基-beta-D-阿拉伯呋喃基尿嘧啶 在 吡啶 、 4-二甲氨基吡啶 作用下， 反应 56.0h， 生成 1-(2-deoxy-2-fluoro-3-O-mesyl-5-O-trityl-β-D-arabinofuranosyl)-5-ethyluracil
  参考文献：
  名称：

  Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors

  摘要：

  Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2,4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 20-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(beta-D-arabinofuranosyl)-4-thio-5hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC50 = 0.5 mu g/mL) and M. bovis (MIC50 = 0.5 mu g/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC50 = 5.0 mu g/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC50 = 1 mu g/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC50 = 10 mu g/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC50 > 100 mu g/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.05.004

文献信息

• Antiviral Activity of Various 1-(2′-Deoxy-β-<scp>d</scp>-lyxofuranosyl), 1-(2′-Fluoro-β-<scp>d</scp>-xylofuranosyl), 1-(3′-Fluoro-β-<scp>d</scp>-arabinofuranosyl), and 2′-Fluoro-2′,3′-didehydro-2′,3′-dideoxyribose Pyrimidine Nucleoside Analogues against Duck Hepatitis B Virus (DHBV) and Human Hepatitis B Virus (HBV) Replication
  作者：Naveen C. Srivastav、Neeraj Shakya、Michelle Mak、Babita Agrawal、D. Lorne Tyrrell、Rakesh Kumar

  DOI：10.1021/jm100803c

  日期：2010.10.14

  3′-fluoroarabinofuranosyl, and 2′-fluoro-2′,3′-didehydro-2′,3′-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy-β-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-β-d-lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)thymine (39), 2′,3′-dideoxy-2′,3′-d

  尽管存在成功的疫苗和抗病毒疗法，但乙型肝炎病毒（HBV）的感染仍然是急性和慢性肝病以及高死亡率的全球主要原因。我们合成并评估了几种lyxofuranosyl，2'-fluorooxylofuranosyl，3'-fluoroarabinofuranosyl和2'-fluoro-2'，3'-didehydro-2'，3'-dideoxyribose嘧啶核苷类似物对乙型肝炎病毒的抗病毒活性。在所检查的化合物中，1-（2-脱氧-β - d-呋喃呋喃糖基）胸腺嘧啶（23），1-（2-脱氧-β - d-呋喃呋喃糖基）-5-三氟甲基尿嘧啶（25），1-（2-脱氧-2-氟-β - d-木呋喃糖基）尿嘧啶（38），1-（2-脱氧-2-氟-β- d-二呋喃呋喃糖基）胸腺嘧啶（39），2'，3'-二脱氧-2'，3'-二脱氢-2'-氟胸苷（48）和2'，3'-二脱氧-2'，3'-二脱氢-2在原代鸭肝细胞中发现'
• Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2′-‘up’ fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors
  作者：Neeraj Shakya、Naveen C. Srivastav、Sudha Bhavanam、Chris Tse、Nancy Desroches、Babita Agrawal、Dennis Y. Kunimoto、Rakesh Kumar

  DOI：10.1016/j.bmc.2012.05.004

  日期：2012.7

  Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2,4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 20-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(beta-D-arabinofuranosyl)-4-thio-5hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC50 = 0.5 mu g/mL) and M. bovis (MIC50 = 0.5 mu g/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC50 = 5.0 mu g/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC50 = 1 mu g/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC50 = 10 mu g/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC50 > 100 mu g/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB. (C) 2012 Elsevier Ltd. All rights reserved.